1. The document discusses drug distribution between blood and tissues, factors affecting it like lipid solubility, and implications of volume of distribution, plasma protein binding, redistribution, and barriers like the blood-brain and placental barriers. 2. Apparent volume of distribution describes the fluid volume required to contain the entire drug dose at the same concentration as plasma, and is affected by factors like lipid solubility and plasma protein binding. 3. Plasma protein binding influences drug availability and can cause drug interactions through displacement, while barriers like the blood-brain and placental barriers control drug passage into sensitive tissues and the fetus.

1. Drug distribution
Dr Naser

2. Objectives
1. Overview of drug distribution
2. Explain apparent volume of distribution
with clinical implications
3Discuss drug binding to plasma proteins and
tissues with clinical implications
4. Explain redistribution
5. Discuss blood brain barrier and Placental
barrier

3. Drug Distribution refers to the Reversible
Transfer of a Drug between the Blood and the
Extra Vascular Fluids and Tissues of the body
(for example, fat, muscle, and brain tissue).

4. DRUG ADMINISTRATION
May get distributed
to…..
Vascular compartment
Total body water
Interstitial fluid compartment
Extracellular space
Intracellular compartments
Body fat
Bones
Placenta
Brain
Plasma proteins
Liver
Many more organs !!!

5. Factors
affecting
distribution
Lipid
solubility
(lipophilicit
y) &
ionization
Capillary
permeability
Binding of
drugs to
plasma
proteins &
tissues
Presence of
tissue
specific
transporters
Cardiac
output and
local blood
flow.

6. Volume of distribution
• Fluid volume that is required to contain the entire
drug in the body at the same concentration
measured in the plasma.
• Calculated by dividing the dose that ultimately gets
into the systemic circulation by the plasma
concentration at time zero (C0)

7. Which means
• If 500 mg of drug reaches circulation…(total amount of drug )
• And if plasma concentration is 0.5 mg/ml
• Vd will be 500/0.5 = 1000 ml.
• Which means you require 1000 ml of fluid to accommodate total 500 mg
of drug at concentration of 0.5 mg/ml.
• At times it can be larger than total blood volume. (when drug
has been stored in peripheral tissues so lower blood concentration).
• At times it can be smaller than or equal to total blood
volume( when drug remains in vascular compartment).

8. Vd(L) =
Total amount administered
Plasma concentration
Total amount administered
Plasma concentration
Vd(L) =
When plasma
concentration
is high….
Vd is low….

9. Vd(L) =
Total amount administered
Plasma concentration
When plasma
concentration
is low….
Vd is high….

10. Distribution into the water
compartments of body
• Plasma compartment:
– Drugs having high molecular weight or extensively
plasma protein bound like heparin Vd= 4L
• Extracellular fluid:
– Low molecular weight but hydrophilic drugs
– Aminoglycosides Vd=14L
• Total body water:
– low molecular weight and lipophilic,
– E.g Ethanol Vd=42 L

12. Apparent Volume of distribution
• A drug rarely associates exclusively with only one
of the water compartments of the body.
• Vast majority of drugs distribute into several
compartments, often avidly binding cellular
components, such as lipids, proteins, and nucleic
acids.
• Thus, the volume into which drugs distribute is
called the apparent volume of distribution (Vd).

13. Plasma protein binding
• Most drugs posses physicochemical affinity for
plasma proteins
– Acidic drugs bind to plasma albumin, basic drugs
bind to 1 acid glycoprotein
– Reversible manner
– Extensive binding serves as a circulating drug
reservoir
– Other proteins to which drugs can bind: globulins,
transferrin, ceruloplasmin, tissue proteins &
nucleoproteins

14. Clinical implications of plasma protein
binding
1. Highly plasma protein bound drugs does not
cross membranes so largely restricted to
vascular compartments (smaller Vd).
2. Temporary storage of the drug which is not
available for any action.
3. High degree of protein binding generally
makes the drug long acting
4. Plasma concentrations of the drug refer to
bound as well as free drug.

15. 5. One drug can bind to many sites on the albumin molecule.
Conversely, more than one drug can bind to the same site.
6. Displacement reactions- (Drug interactions)
– Salicylates displace sulfonylureas & methotrexate.
– Indomethacin, phenytoin displace warfarin.
– Sulfonamides and vit K displace bilirubin(kernicterus in neonates) .
7. In hypoalbuminemia, reduced binding leads to high
concentrations of free drug e.g. phenytoin and furosemide.
8. Other diseases: e.g. phenytoin and pethidine binding is
reduced in uraemia;
Clinical implications of plasma protein
binding

16. Drugs highly bound to plasma proteins
• To albumin
• Barbiturates
• Benzodiazepines
• NSAIDs
• Valproic acid
• Phenytoin
• Penicillins
• Sulfonamides
• Tetracyclines
• Warfarin
• To α1 acid glycoprotein
• β-blockers
• Bupivacaine
• Lidocaine
• Disopyramide ,
• Imipramine
• Methadone
• Prazosin
• Quinidine
• Verapamil

17. Clinical implications of volume of distribution
• Dialysis is not very useful for drugs with high
Vd e.g digoxin, imipramine
• It helps in estimating the total amount of drug
at any time
amount of drug = Vd X plasma conc of drug at
certain time
• Vd is important to determine the loading dose
Loading dose = Vd X desired concentration

18. Drugs concentrated in body tissues
• Digoxin, emetine: Skeletal muscles, heart,
liver, kidney
• Chloroquine: retina and liver
• Iodine: Thyroid
• Chlorpromazine: eye
• Atropine: iris
• Tetracyclines: Bone and teeth
• Thiopentone , DDT: Adipose tissue

19. Redistribution
• Highly lipid-soluble drugs get initially distributed to organs
with high blood flow ( brain, heart, kidney) & later into bulky
less vascular tissues (muscle, fat)
• So plasma concentration falls and the drug is withdrawn from
these sites
• If the site of action of drug is one of highly perfused organs,
redistribution may result in termination of drug action.
• Greater the lipid solubility faster is the redistribution of drug.
• Anaesthetic action of thiopentone sod. injected i.v. is
terminated in few minutes due to redistribution.
• To overcome , give continous infusion

21. PLASMA HALF LIFE
• It is the time taken for the plasma concentration or amount of the drug
present in the body to reduce to 50% of previous level.
PLASMACONC
TIME
ALPHA = DISTRIBUTION PHASE
BETA = ELIIMINATION PHASE
Clinically t ½ that is
calculated from BETA
ELIMINATION PHASE is
considered as t ½ of
drug.

22. At peak  blood concentration will be 100 %
After 1 half life  blood concentration will be 50 %
After 2 half lives  blood concentration will be 25 %
After 3 half lives  blood concentration will be 12.5 %
After 4 half lives  blood concentration will be 6.25 %
After 5 half lives  blood concentration will be 3.125 %
So after 4-5 half lives
drug will be almost
completely eliminated
from the body
If you administer a
drug before that
there will be
accumulation of
the drug in the
body.

23. Blood brain barrier

24. Functions and Properties of the BBB
• Protects the brain from "foreign substances"
in the blood that may injure the brain.
• Protects the brain from hormones and
neurotransmitters in the rest of the body.
• Maintains a constant environment for the
brain.

25. Properties of drugs that can cross BBB
• low molecular weight
• High degree of lipid solubility
• Non ionized
• Tertiary structure and
• Free drug

26. Placental Barrier
• Lipoidal and allows free passage of lipophilic
drugs
• P Glycoprotein limits exposure to maternally
administered drugs
• Also placenta is site of metabolism- lowers
exposure to drugs
• Incomplete barrier
• Congenital anomalies

27. Summary
1. Overview of drug distribution
2. Apparent volume of distribution with clinical
implications
3 Drug binding to plasma proteins and tissues
with clinical implications
4. Redistribution
5. BBB and Placental barrier